Characteristics and treatment preferences of individuals with opioid use disorder seeking to transition from buprenorphine to extended‐release naltrexone in a residential setting

Abstract Background and Objectives Treatment for individuals receiving medication for opioid use disorder (MOUD) should follow an informed patient‐centered approach. To better support patient autonomy in the decision‐making process, clinicians should be aware of patient preferences and be prepared to educate and assist patients in transitioning from one MOUD to another, when clinically indicated. This posthoc analysis describes the characteristics of clinical trial participants (NCT02696434) with a history of opioid use disorder (OUD) seeking to transition from buprenorphine (BUP) to extended‐release naltrexone (XR‐NTX). Methods The posthoc analysis included adults with OUD currently receiving BUP (≤8 mg/day) and seeking transition to XR‐NTX (N = 101) in a residential setting. Baseline participant characteristics and OUD treatment history were reviewed. All patients completed a screening questionnaire that asked about their reasons for seeking transition to XR‐NTX and for choosing BUP. Results The most common reasons for initiating a transition to XR‐NTX were “Seeking to be opioid‐free” (63.4%) and “Tired of daily pill taking” (25.7%). Positive predictors of transition included a more extensive BUP treatment history and a history of prescription opioid abuse. Most participants stated they were not aware of XR‐NTX as a treatment option when initiating BUP (78.2%). Discussions and Conclusions Patients' reasons for seeking XR‐NTX transition, more extensive BUP treatment history, and a history of prescription opioid abuse, may positively predict outcomes. Scientific Significance These findings may assist clinicians in optimizing outcomes of the BUP to XR‐NTX transition and supporting patients to make better informed MOUD decisions.


INTRODUCTION
For individuals receiving medication for opioid use disorder (MOUD), treatment needs and medication preference may change over the course of their recovery, and it is recommended that treatment decisions follow an informed patient-centered approach. However, involving patients in the clinical decision-making process may only occur at a minority of substance use disorder clinics. 1 To support patient autonomy, it is important that clinicians be aware of expressed patient preferences and be prepared to educate and assist patients, when clinically indicated, in transitioning from one MOUD to another. All US Food and Drug Administration (FDA)-approved MOUDs (methadone, buprenorphine [BUP], and extended-release naltrexone [XR-NTX]) are effective and should be considered by all patients as potential treatment options (https://www.asam.org/ Quality-Science/quality/2020-national-practice-guideline).
For individuals on MOUD, a survey study found that 62% (90/145) had high interest in discontinuing treatment; this intention was associated with having discussed this option with a number of different people (e.g., prescribing doctor, family/friend, case manager, general practitioner). 2 However, barriers to discontinuation include worry about withdrawal symptoms and fear of relapse. 2,3 For individuals seeking to discontinue BUP, the Substance Abuse and Mental Health Services Administration (https://www.samhsa.gov/, Tip 63) recommends that patients be counseled about the risk of relapse, be monitored during and after BUP dose taper, and be urged to consider antagonist therapy with XR-NTX. In particular, patient education about the benefits and challenges of discontinuing BUP should include a discussion of the risks of overdose and death and the high rates of relapse observed when patients discontinue BUP without additional MOUD support. 4,5 XR-NTX, a once-monthly injectable medication, is indicated for the prevention of relapse to opioid dependence following opioid detoxification. A clinical trial evaluated 7-day transition regimens for individuals with a history of opioid use disorder (OUD) currently receiving BUP treatment and seeking to transition from BUP to XR-NTX; overall, 72% of participants in this study successfully received XR-NTX. 5 In this posthoc analysis, we describe the characteristics of participants in this study, including their reasons for seeking to transition from BUP to XR-NTX.

Study design
This Phase 3, multicenter, double-blind, placebo-controlled, randomized, hybrid residential-outpatient trial of adults with OUD currently receiving BUP treatment and transitioning from BUP to XR-NTX (VIVITROL ® , Alkermes, Inc.; ClinicalTrials.gov identifier: NCT02696434) was conducted from May 2016 to November 2017. 5 The study protocol has been described in detail previously. 5 The study included a 7-day residential induction onto XR-NTX (Days 1-7, consisting of standing doses of ancillary medications [clonidine, clonazepam, trazodone], a descending taper of BUP, and transition regimens that included ascending doses of oral NTX vs. placebo), followed by XR-NTX injection (Day 8), and discharge. Screening (including medical/ psychiatric assessment and review of BUP treatment course) was from Days −26 to −6 (outpatient), followed by lead-in BUP stabilization on ≤4 mg daily. Baseline was on Day 1 (residential).

Participants
The study participants (N = 101) have been characterized previously. 5 The sample was recruited through radio, print, and digital advertisements, as well as through word-of-mouth referrals at sites that offered clinical treatment for OUD. The key inclusion criteria in-

Participant characteristics
In this posthoc analysis, we reviewed the baseline participant characteristics (previously reported by Comer et al. 5 ) and OUD treatment history.

Baseline participant characteristics
As reported by Comer et al., 5

Treatment history of participants
Nearly one-half (43/101; 42.6%) of participants had a history of OUD for more than 5 years (Figure 1a). 5 The most commonly used opioids before BUP treatment were intravenous heroin, intranasal heroin, and oxycodone ( Figure 1b

Reasons for seeking to transition from BUP to XR-NTX
The most commonly reported reasons for wanting to transition from BUP to XR-NTX were "Seeking to be opioid-free" (63.4%) and "Tired of daily pill taking" (25.7%) ( Figure 3a). Participants' reasons for wanting to transition from BUP to XR-NTX did not differ based on daily BUP dose (8 vs. <8 mg), BUP treatment duration (6 months to 2 years vs. >2 years), history of opioid use (heroin vs. prescription opioids), gender (female vs. male), or age (median age ≤34 vs.

Baseline predictors of successful transition from BUP to XR-NTX
The likelihood of transition from BUP to XR-NTX was predicted using descriptive statistics. Of the 101 study participants, 72.3% (n = 73) successfully transitioned from BUP to NTX. The responses "Seeking to be opioid-free" and "Tired of daily pill taking," represented by 65.8% (48/73) and 25.7% (18/73) of transitioned participants, respectively, were associated with a higher likelihood of transition from BUP to XR-NTX than any of the reference combination responses ("Cost considerations," "Side effects from BUP," "Using opioids/lapses while on BUP"), represented by 9.6% (7/73). Successful transition from BUP to XR-NTX was seen in 75% of 64 (n = 48) study participants who responded, "Seeking to be opioid-free," 69.2% of 26 (n = 18) study participants who responded, "Tired of daily pill taking," and 63.6% of 11 (n = 7) study participants who responded, "Cost  Awareness of XR-NTX as a treatment option More than three-quarters of participants (79/101; 78.2%) stated that they had not been aware of XR-NTX as a treatment option when they had first initiated BUP treatment (Figure 3b). Other reasons for choosing BUP as the initial treatment included a decision to avoid inpatient detoxification ("Seeking outpatient detox/transition to medication-assisted treatment," 6/101; 5.9%) and "Cost considerations" (6/101; 5.9%).

DISCUSSION
In this study of individuals receiving BUP and seeking XR-NTX treatment, participants most commonly had a history of heroin use and a diagnosis of OUD for more than 5 years, were on their first course of BUP, and were seeking to be opioid-free after at least 1 year of BUP treatment. In addition, more than one-third of otherwise treatment-stable individuals (maintained on ≤8 mg/day BUP for F I G U R E 3 Questionnaire results of participants seeking to transition from buprenorphine (BUP) to extended-release naltrexone (XR-NTX) (as per a questionnaire with pre-populated answer choices). (a) Primary reason for the transition from BUP to XR-NTX (at screening). Participants were asked, "What is your main reason for wanting to transition from BUP to VIVITROL?" Answer choices consisted of the following: "Seeking to be opioid-free," "Tired of daily pill taking," "Side effects from BUP," "Still experiencing cravings for opioids," "Using opioids/lapses while on BUP," "Work-related concerns," "Childcare-related concerns," "Transportation is inconvenient," "Hassle of filling prescriptions," "Concerns about BUP being lost/stolen," "BUP requires too many appointments," "Cost considerations," or "Other." The reported "Side effects from BUP" were sweats/chills (n = 2), dizziness/lightheadedness (n = 1), drowsiness/sleepiness (n = 1), other (n = 1), and mental slowing (n = 1). (b) Awareness of XR-NTX as a treatment option when BUP was initiated (at screening). Participants were asked "Why did you choose BUP?" Answer choices consisted of the following: "Not aware of VIVITROL at the time," "Seeking outpatient detox/transition to medication-assisted treatment," "Cost considerations," "Provider encourages BUP over other treatments," "Positive experience with non-prescription 'street' BUP," "BUP was available by prescription from doctor's office," "Concerns about withdrawal symptoms on VIVITROL," or "Other." For (a) and (b), only one answer could be selected, and "None of the above" was not included as an option The results of the present study demonstrate that, in the course of long-term management of OUD, many patients may choose to transition from one MOUD to another. Assessment of patients' beliefs and goals is important to fostering continued treatment engagement. We found that endorsing a desire to become opioid-free or to discontinue pill taking, among patients who had been treated with BUP for more than 12 months for prescription opioid misuse, predicted a successful transition from BUP to XR-NTX. The finding that a past history of prescription opioid use, pre-dating buprenorphine treatment, predicts successful transition to XR-NTX extends earlier research findings that a current history of lower severity opioid dependence is a positive predictor of induction from untreated OUD onto XR-NTX. 6 Clinicians can play a significant role in facilitating patient-centered care practices for OUD, particularly when supporting the patient's choice of treatment. 8 A survey of patients enrolled in BUP treatment found that the decision to seek discontinuation was associated with having engaged in a recent discussion with a clinician. 9 However, clinicians may not exert equal influence with respect to all MOUD decisions. For example, a semistructured interview study of individuals with a history of MOUD found that patients became interested in BUP treatment through peer education; in contrast, patients became interested in XR-NTX treatment through clinicians. 10 A patient's personal beliefs about the efficacy and safety of a treatment, or its consistency with the goal of being opioidfree, may play a major role in MOUD decision-making. 7 Personal barriers specific to treatment should also be considered; in addition to a lack of awareness of the medication, the barriers to XR-NTX treatment often include limited access to medically supervised detoxification and fear of, or lack of interest in, antagonist treatment. 11 This study is inherently limited as a posthoc analysis. In addition, we collected data at screening and baseline (study entry) from a specific population of patients who were interested in starting antagonist treatment for OUD, as this was a criterion for study entry; only data from participants included in the study are presented.

ACKNOWLEDGMENTS
This study was sponsored by Alkermes, Inc., the manufacturer/ licensee of XR-NTX. Alkermes, Inc. was involved in the study design, data collection, data analysis, and preparation of the manuscript.
The authors thank the investigators and participants for their contributions to this study. Data analysis support was provided by Bao

DATA AVAILABILITY STATEMENT
The data collected in this study are proprietary to Alkermes, Inc.
Alkermes, Inc. is committed to public sharing of data in accordance with applicable regulations and laws.